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Peptidomimetic modulators of BACE1


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Juliano, JP, Small, DH ORCID: 0000-0002-6945-2190 and Aguilar, M-I 2020 , 'Peptidomimetic modulators of BACE1' , Australian Journal of Chemistry, vol. 73, no. 4 , pp. 366-376 , doi: 10.1071/CH19594.

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The β-site APP Cleaving enzyme 1 (BACE1) is a membrane-associated aspartyl protease which mediates the production of amyloid-β (Aβ), a major component of amyloid plaques in the Alzheimer's disease brain. We have synthesised and characterised a series of peptidomimetic analogues of BACE substrates that incorporate two distinct stabilising structures. To demonstrate the potential activity of these compounds, a variety of assaying strategies were used to investigate cleavage susceptibility and inhibition potency under competitive and non-competitive conditions. β-Amino acids and scissile site N-methylation were incorporated into peptide substrate templates as transition state isostere (TSI) substitutes by positional scanning to generate series of non-TSI β-peptidomimetics. The amino acid sequences flanking the β-cleavage site within APP carrying the Swedish double mutation (APPSW), Neuregulin, the synthetic hydroxyethylene-based TSI peptide inhibitor OM99-2, and the high affinity peptide sequence SEISYEVEFR, served as the four substrate templates from which over 60 peptides were designed and synthesised by solid phase peptide synthesis. A quenched fluorescent substrate BACE1 assay in conjunction with liquid chromatography-mass spectrometry (LC-MS) analysis was established to investigate cleavage susceptibility and inhibition potency under competitive and non-competitive conditions. It was determined that β-amino acids substituted at the P1 scissile site position within known peptide substrates were resistant to proteolysis, and particular substitutions induced a concentration-dependent stimulation of BACE1, indicating a possible modulatory role of native BACE1 substrates.

Item Type: Article
Authors/Creators:Juliano, JP and Small, DH and Aguilar, M-I
Journal or Publication Title: Australian Journal of Chemistry
Publisher: CSIRO Publishing
ISSN: 0004-9425
DOI / ID Number: 10.1071/CH19594
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Copyright CSIRO 2020

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